NM_021073.4:c.976C>A

Variant names:

• chr6-55774100-G-T
• rs746918830
• NM_021073.4:c.976C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_021073.4(BMP5):​c.976C>A​(p.Arg326Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R326C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BMP5 NM_021073.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.99
• Publications: 0 publications found

Genes affected

BMP5 (HGNC:1072): (bone morphogenetic protein 5) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer, which plays a role in bone and cartilage development. Polymorphisms in this gene may be associated with osteoarthritis in human patients. This gene is differentially regulated in multiple human cancers. This gene encodes distinct protein isoforms that may be similarly proteolytically processed. [provided by RefSeq, Jul 2016]

BMP5 Gene-Disease associations (from GenCC):

• dysostosis

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021073.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP5	NM_021073.4	MANE Select	c.976C>A	p.Arg326Ser	missense	Exon 4 of 7	NP_066551.1	P22003-1
	BMP5	NM_001329754.2		c.976C>A	p.Arg326Ser	missense	Exon 4 of 6	NP_001316683.1	P22003-2
	BMP5	NM_001329756.2		c.976C>A	p.Arg326Ser	missense	Exon 4 of 5	NP_001316685.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP5	ENST00000370830.4	TSL:1 MANE Select	c.976C>A	p.Arg326Ser	missense	Exon 4 of 7	ENSP00000359866.3	P22003-1
	BMP5	ENST00000901523.1		c.976C>A	p.Arg326Ser	missense	Exon 4 of 6	ENSP00000571582.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461014 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726818

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111478

Other (OTH) AF: 0.00 AC: 0 AN: 60348

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.66	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		5.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.38
Sift	Benign	0.14	T
Sift4G	Benign	0.10	T
Polyphen		0.99	D
Vest4		0.72
MutPred		0.40		Gain of phosphorylation at R326 (P = 0.0132)
MVP		0.87
MPC		0.53
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.40
gMVP		0.62
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs746918830; hg19: chr6-55638898; COSMIC: COSV100896241;